TRPV4 Channels stimulate Ca²⁺-induced Ca²⁺ release in astrocytic endfeet and amplify neurovascular coupling responses

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 15; pp. 6157 - 6162
• Main Authors: Dunn, Kathryn M., Hill-Eubanks, David C., Liedtke, Wolfgang B., Nelson, Mark T.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences 09.04.2013; National Acad Sciences
• Subjects: Agonists; Animals; Arterioles; Astrocytes; Astrocytes - cytology; Biological and medical sciences; Biological Sciences; Blood flow; Brain; Brain - metabolism; Brain - pathology; Calcium; Calcium - metabolism; Calcium Signaling; Central Nervous System - physiology; Fluorescence; Fundamental and applied biological sciences. Psychology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons - metabolism; Oscillometry; Receptors; TRPV Cation Channels - metabolism; Vasodilation; Vertebrates: nervous system and sense organs; Wave propagation; Microcirculation; Calcium; Arteriole; Neuroglia; parenchymal arteriole; Circulatory system; Astrocyte; Release
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1216514110

In the CNS, astrocytes are sensory and regulatory hubs that play important roles in cerebral homeostatic processes, including matching local cerebral blood flow to neuronal metabolism (neurovascular coupling). These cells possess a highly branched network of processes that project from the soma to neuronal synapses as well as to arterioles and capillaries, where they terminate in "endfeet" that encase the blood vessels. Ca²⁺ signaling within the endfoot mediates neurovascular coupling; thus, these functional microdomains control vascular tone and local perfusion in the brain. Transient receptor potential vanilloid 4 (TRPV4) channels—nonselective cation channels with considerable Ca²⁺ conductance—have been identified in astrocytes, but their function is largely unknown. We sought to characterize the influence of TRPV4 channels on Ca²⁺ dynamics in the astrocytic endfoot microdomain and assess their role in neurovascular coupling. We identified local TRPV4-mediated Ca²⁺ oscillations in endfeet and further found that TRPV4 Ca²⁺ signals are amplified and propagated by Ca²⁺-induced Ca²⁺ release from inositol trisphosphate receptors (IP₃Rs). Moreover, TRPV4-mediated Ca²⁺ influx contributes to the endfoot Ca²⁺ response to neuronal activation, enhancing the accompanying vasodilation. Our results identify a dynamic synergy between TRPV4 channels and IP₃Rs in astrocyte endfeet and demonstrate that TRPV4 channels are engaged in and contribute to neurovascular coupling.